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MCD Cancer > Colorectal Cancer > Flashcards

Colorectal Cancer Flashcards

1
Q

describe the epidemiology of colorectal cancer

A
  • major cancer of the developed world
  • 4th most common cancer worldwide and the 2nd leading cause of death (16,000/year) by cancer overall (behind lung cancer).
  • genetic and environmental components involved
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2
Q

what is the function of the colon?

A

o Extraction of water from faeces
– electrolyte balance.
o Faecal reservoir, reduce defaecation frequency
o Bacterial digestion for vitamin production (B and K)

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3
Q

describe the general anatomy of the colon

A

Smooth folded mucosa with thick muscle layer

  • The thick mucosa has deep crypts, but there are no villi
  • The epithelium is formed of columnar absorptive cells with a striated border, many goblet cells, endocrine cells and basal stem cells, but no Paneth cells.
  • The surface epithelial cells are sloughed into the lumen, and have to be replaced around every 6 days.
  • mesenchymal support cells
  • lamina propria and submucosa
  • paneth cells are seen in the base of crypts of the caecum and ascending colon
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4
Q

what are cancers of the colon called?

A

adenocarcinomas (glandular)

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5
Q

where does cell proliferation for colon regeneration take place?

A

cell divide at the crypts (where stem cells are found) and move up

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6
Q

what is the turnover of the colon? what does it leave vulnerable to?

A

2-5 million cells die per minute therefore has a high proliferation rate making it vulnerable to mutation

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7
Q

what is the effect of an APC mutation?

A

prevents cell loss and causes cell proliferation

can no longer degrade free beta catenin which will now bind to LEF-1 and cause gene expression and proliferation

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8
Q

what comprises the normal protective mechanisms to preventing cancer?

A

normal loss of cells
DNA monitors
repair enzymes

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9
Q

what is a polyp?

A

any projection from the mucosal surface into hollow viscus

it may be: hyper plastic/neoplastic /inflammatory/hamartomatous

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10
Q

what are the types of polyps?

A
  • Metaplastic/hyperplastic.
  • Adenomas.
  • Juvenile, Peutz Jeghers, lipomas,
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11
Q

what is an adenoma?

A

a benign neoplasm of the mucosa

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12
Q

describe hyperplastic polyps

A 
 Very common growths <0.5cm.
 Constitute 90% of all colon polyps.
 Often come in multiples.
 They have NO malignant potential 
- 15% with K-ras mutation
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13
Q

what are the 4 types of colonic adenomas?

A 
o Tubular 
– 90% adenomas (>75% tubular).
o Villous
 – (>50% villous).
o Tubulovillous (mixed of the first two)
– 10% adenoma (25-50% villous).
o Other 
– flat, serrated.

the more villous the worse

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14
Q

in what two ways can an adenoma look like?

A

o pedunculated
- adenoma on a stalk

o sessile
- flat and raised; can both be tubular, villous, etc

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15
Q

describe the microstructure of tubular adenomas

A

These are often well defined and pedunculated

 Columnar cells with :
- nuclear enlargement
- elongation
- multi-layering
- loss of polarity.
 Proliferation.
 Reduced differentiation.
 Complexity/disorganisation of architecture.
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16
Q

describe the microstructure of villous adenomas

A

These are often larger, more diffuse and difficult to sample

 Mucinous cells with:
- nuclear enlargement
- elongation
- multi-layering
- loss of polarity.
 Exophytic 
– front-like extensions.
 Rarely, may hyper-secrete resulting in excess mucus discharge and hypokalaemia.
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17
Q

what is dysplasia?

A

abnormal growth of cells with features of cancer i.e. showing malignancy features

remember malignant epithelial cells have acquired 3 abilities:

1) Extracellular (stromal) matrix degradation (especially basement membranes)
2) Adhesion to degraded or new extracellular matrix (ECM)
3) Ability to move into the newly degraded ECM

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18
Q

what is Familial Adenomatous Polyposis (FAP)?

A

o 5q21 gene mutation.

o Site of mutation determines clinical variants – i.e. classic, attenuated, Gardner, Turcot.

o Many patients of FAP have a prophylactic colectomy (<30)

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19
Q

describe the malignancy potential of adenomas

A
  • 25% of adults have adenomas at age 50
  • 5% become cancers if left
  • Adenomas precede carcinomas by about 10-15 years
  • Larger polyps have a greater chance of becoming cancerous than smaller polyps
  • Cancers stay at a curable stage for about 2 years
  • Most colorectal cancers arise from adenomas with 10-30% of CRCs having a residual adenoma
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20
Q

what is involved in the carcinoma pathway from adenoma?

A
  • APC, K-Ras, Smads, p53, telomerase activation.

- micro satellite instability

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21
Q

what does microsatellite instability mean?

A

Microsatellites are repeat sequences prone to misalignment
Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis.

leads to HNPCC

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22
Q

what must occur for cancer to be cured by mismatch repair gene faults (microsatelllite)?

A

2 hits as they are recessive genes

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23
Q

what is HNPCC and what does it affect?

A

Hereditary Non-Polyposis Colorectal Cancer

– germ-line mutations

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24
Q

what are the main pathways to colorectal cancer with genetic predisposition?

A

o FAP – inactivation of APC TSG.

o HNPCC – microsatellite instability.

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25
Q

what genes are involved as the adenoma progresses to the carcinoma?

A
  • initially APC, mismatch repair genes like MSH2
    then beta catenin
  • then K-ras and p53 become involved (deleted)
  • SMAD loss
  • E cadherin mutatin
  • at the carcinoma stage, many genes are involved
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26
Q

what are the dietary factors that predispose to colonic carcinoma?

A

high fat
low fibre
high red meat
refined carbohydrates.

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27
Q

how can food exacerbate the carcinoma risk?

A
  • high amount of bioactive substance
  • can contain carcinogens (as well as anticancer agents)
  • heating food induces chemical changes that induce mutagenic chemicals
  • bacteria also modify residues
  • Heterocyclic Amine oxidation leads to mutagenesis

40% of cancers due to diet

28
Q

what dietary deficiencies increase the risk of colorectal cancer?

A

o Folates: co-enzymes needed for nucleotide synthesis and DNA methylation.

o MTHFR –Methylenetetrahydrofolate Reductase:

  • Deficiency leads to disruption in DNA synthesis causing DNA instability therefore mutation.
  • Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation therefore gene activating and silencing effects.
29
Q

what are the anti-carcinogenic elements in food?

A 
o	Vitamin C and E 
– ROS scavengers.
o	Isothiocyanates
 – cruciferous vegetables.
o	Polyphenols
 – green tea (EGCG-induced telomerase activity) and fruit juice.
- Garlic associated apoptosis.
30
Q

how are polyphenols anti-carcinogenic?

A

activate MAPK pathways by regulating phase 2 metabolisms to detoxify enzymes as well as other genes and thus reduce DNA oxidation

31
Q

clinical presentation:

how does someone with colorectal cancer present?

A 
 Change in bowel habit.
 Pre-rectal bleeding.				
 Unexplained iron deficient anaemia.
 Other 
- mucus pre-rectal production
-bloating
- cramps (“colic”)
- weight loss
- fatigue.

Patients and doctors rationalise these symptoms as getting old!

32
Q

what may present within larger polypoid adenomas?

A

small carcinomas

33
Q

how does colon cancer affect different parts of the colon and rectum (distribution)?

A

o Caecum/ascending colon 22%.
o Transverse colon 11%.
o Descending colon 6%.
o Recto-sigmoid 55%.

mostly rectum

34
Q

what are some microscopic features of carcinomas in the colon?

A

 Mucinous carcinoma.
 Signet ring cell carcinoma.
 Neuroendocrine carcinoma (rare).

35
Q

how is colorectal cancer graded?

A

Defined by the proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina

o 10% Well differentiated.
o 70% Moderately differentiated.
o 20% Poorly differentiated.

TNM system

36
Q

how does the Dukes classification grade colorectal cancer?

A

o Dukes A

  • growth limited to wall
  • nodes negative.

o Dukes B
- growth beyond Muscularis propria, nodes negative.

o Dukes C1

  • nodes positive,
  • apical lymph node negative.

o Dukes C2
- apical lymph nodes (LN) positive.

prognosis worsens as you go down

37
Q

what are the negative (not good) clinical features affecting prognosis?

A

1) Age <30 (earlier onset)
2) Preoperative serum CEA (high)
3) Distant metastasis
4) worsened with bowel obstruction/perforation

38
Q

what are clinical features with an improved prognosis

A

1) Diagnosis of asymptomatic patients
2) Rectal bleeding as presenting symptom
3) present local inflammatory/immunological response

39
Q

what are all the clinical feature of CRC affecting prognosis?

A 
	Diagnosis of asymptomatic patients	
	Rectal bleeding as presenting symptom	
	Bowel obstruction			
	Tumour location			
	Age <30			
	Preoperative serum CEA (high)			
	Distant metastasis
40
Q

what are the pathological features that give a positive prognosis?

A

 Decreased bowel wall penetration
 Decreased regional LN involvement
 Local inflammation and
immunologic reaction

41
Q

what are the pathological features that give a negative prognosis?

A 
	Poor differentiation			
	Mucinous/signed ring cell type		
	Venous invasion			
	Lymphatic invasion			
	Peri-neural invasion
42
Q

what are treatment options according the stage of cancer?

A

surgery is an option at a stages

2- 5FU
3- 5FU/leucovorin
4- metastatectomy/chemo/palliative RT

43
Q

what are some prerequisites for screening for high CRC risk?

A
  • Previous adenoma.
  • 1st degree relative affected by CRC before age 45.
  • Two affected 1st degree relatives.
  • Evidence of dominant familial cancer trait.
  • UC and Crohn’s disease
44
Q

what is the definition of screening?

A

Screening is the practice of investigating apparently healthy individuals with the object of identifying previously unknown disease

45
Q

what is the NHS screening programme for colon cancer?

A

They look for Faecal Occult Blood.

From 55+, a FOB test kit is sent to people.
If positive, an endoscopy is performed.

55-60yo = sigmoidoscopy.
60+ = full colonoscopy.
46
Q

what is the criteria for screening?

A

o Condition should be important in respect to the seriousness and/or frequency.
o Natural history of the disease must be known – to identify where/if screening and intervention takes place.
o Test must be simple, acceptable, sensitive, selective and cost-effective.
o Screening population should have equal access to the screening procedure.

47
Q

which vitamins are sourced from bacterial digestion in colon?

A

B/K

48
Q

describe the epithelium of the colon

A
  • simple columnar
  • extensive microvilli on villi
  • goblet cells secrete mucin
49
Q

how are shed enterocytes replaced by the colon?

A

regenerative crypts of Lieberkuhn are found the base of the villi

these generate new replacement cells

50
Q

which genes are associated with the adenoma carcinoma sequence ?

A
  • APC (germline mutation)
  • MSH2 (germline mutation)
  • Beta catenin (somatic mutation)
  • K-ras (somatic mutation)–> adenoma
  • p53 (loss)–> carcinoma
    and telomerase
51
Q

what is the cause of hereditary nonpolyposis colorectal cancer?

what genes are involved?

A

microsatellite instability:
- repeat sequences prone to misalignment

MLH-1, MSH-2 (TSGs) that become mutated

52
Q

what are the features of adenoma?

A

(k-ras mutation)

  • Hyperchromic and enlarged nuclei
  • Elongation and multilayering of cells
  • Loss of polarity
  • Increased proliferation
  • Reduced differentiation
  • Loss of complexity, disorganisation of architecture
  • Histologically: very purple cells
53
Q

what are the stages of colon cancer development?

A

1) normal colon
(has inherited or acquired mutations i.e. first hit)
2) high risk mucosa
(methylation abnormalities; inactivation of normal alleles i.e. second hit)
3) adenoma
(proto-oncogene mutations and loss of suppressor genes; overexpression of COX-2)
4) carcinoma
(additional mutations and chromosomal alterations)

54
Q

what mutation can be a first hit on the normal colon?

A

APC

55
Q

what mutation can be the second hit creating the high risk mucosa?

A

APC or beta catenin

56
Q

what mutations involved in adenoma?

A

K-ras (onco)

57
Q

what mutations is additional in making the cancer worse (carcinoma) ?

A

telomerase and other genes

58
Q

what is the main clinical presentation of colorectal cancer?

A
  • Change in bowel habit
  • Bleeding Pre-rectal
  • Unexplained iron deficiency anaemia
  • Other changes:
    Mucus production pre-rectal
    Bloating
    Cramps
    Weight loss
59
Q

for those with positive CRC, what is the different colonoscopy offered for different age groups?

  • 60-75
  • 55-60
A

60-75–> colonoscopy

55-60–> sigmoidoscopy (not full colon)

check for pre rectal bleeding (anaemia)

60
Q

Duke A stage

A
  • limited to bowel wall
  • no deeper than submucosa
  • nodes involvement negative
61
Q

Duke B stage

A

B1: - not through bowel wall: growth beyond muscularis mucosa into muscularis propria
- no nodes involved

B2: through bowel wall but no lymph

62
Q

Duke C1 stage

A
  • not through bowel wall but
    node involvement positive
  • apical lymph node negative
63
Q

Duke C2 stage

A
  • through bowel wall
  • apical lymph node positive

apical lymph nodes are located near pec minor

64
Q

what pathological features are used to determine the prognosis of CR cancer?

A
  • depth of bowel penetration
  • degree of differentiation
  • venous, lymphatic involvement
  • local inflammatory response/immunological response

these help stage the cancer in the Duke’s classification

65
Q

what is the hallmark of invasion in adenoma?

A

penetration of thin muscularis mucosae

layers:

  • epithelia (lamina propria)
  • muscularis mucosae
  • submucosa
  • mucularis propria

once beyond the muscularis mucosae they have access to the lymphatics and capillaries

MCD Cancer (17 decks)

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